Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].[NH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][N:32]=1>>[NH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:13][C:10]2[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]3[CH:6]=[CH:5][C:4]([O:17][CH2:18][CH2:19][CH2:20][S:21]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)(=[O:22])=[O:23])=[C:3]([O:2][CH3:1])[C:12]=3[N:11]=2)=[O:36])=[CH:33][N:32]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: COc1c(OCCCS(=O)(=O)N2CCOCC2)ccc2c1N=C(N)N1CCN=C21
Product: COc1c(OCCCS(=O)(=O)N2CCOCC2)ccc2c1N=C(NC(=O)c1ccc(N)nc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 16, Step 2 was used to prepare the title compound from 7-methoxy-8-[3-(morpholin-4-ylsulfonyl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Step 1) and 6-aminonicotinic acid. High vacuum drying gave the title compound (122 mg, 63%): HPLC MS RT=1.96 min, MH+=544.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.22-2.27 (2H, m), 3.15-3.18 (4H, m), 3.24-3.29 (2H, m), 3.61-3.65 (4H, m), 3.99 (3H, s), 4.24-4.27 (2H, m), 4.38 (2H, t), 4.48-4.52 (2H, m), 7.05 (1H, d), 7.47 (1H, d), 8.04 (1H, d), 8.49 (1H, dd), 8.78 (1H, d).
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[CH2:8][CH2:7]1)C.O1CCCC1.O.[OH-].[Li+].Cl>O>[CH:12]1([N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][C:4]([OH:16])=[O:3])[CH2:11][CH2:10]2)[CH2:13][CH2:14][CH2:15]1
Reactant: CCOC(=O)CC1CCN(C2CCC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 130.7 %

Procedure:
To a stirred mixture of (1-cyclobutyl piperidin-4-yl) acetic acid ethyl ester (652.9 mg, 2.90 mmol, obtained in above step), tetrahydrofuran (6 mL) and water (6.0 mL) cooled at 0° C. lithium hydroxide monohydrate (133 mg, 3.19 mmol) was added in a single lot. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled again to 0° C. and acidified with 2N hydrochloric acid to pH: 2-3. The volatiles were removed under reduced pressure and the traces of water were removed by azeotropic distillation with toluene to obtain (1-cyclobutyl piperidin-4-yl) acetic acid (747.9 mg).
Reaction SMILES: [Br-].[CH3:2][CH:3]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)/C=C/CC.O1[CH2:31][CH2:30][CH2:29][CH2:28]1.C([Li])CCC.[CH3:37]/[C:38](=[CH:41]\[C:42](\[CH3:45])=[CH:43]\[CH3:44])/[CH:39]=O>CCCCC.O>[CH3:28]/[C:29](/[CH:37]=[C:38](\[CH3:39])/[CH:41]=[C:42](\[CH3:45])/[CH:43]=[CH:44]/[CH2:2][CH3:3])=[CH:30]\[CH3:31]
Reactant: CC/C=C/C(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Reactant: C/C=C(C)/C=C(\C)C=O
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCC
Product: C/C=C(C)/C=C(C)/C=C(C)/C=C/CC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(1-Methyl-(E)-2-pentenyl)triphenylphosphonium bromide (0.40 g, 0.0009 mole), from Example 11, was added to a flask with 2 ml dry tetrahydrofuran. The reaction was run under nitrogen, and the flask was equipped with a magnetic stirrer. The mixture was cooled over ice, and butyllithium (2.5 m in hexane) was added dropwise until the color change became permanent; then an additional 0.4 ml (0.001 mole) was added. After 5 min, 100 mg (0.0008 mole) of 2,4-dimethyl-(E,E)-2,4-hexadienal (4, R1 =H) was added. The mixture was warmed to room temperature, stirred for 2 hr, then cooled over ice again. Water (1 ml) and pentane (3 ml) were added. The aqueous layer was washed twice with 2 ml pentane. The combined organic layers were washed three times with water and dried over Na2SO4. After the product was passed through a silica column with hexane, both the (E,E,E,E) and (E,E,Z,E) isomers were present (47% and ca. 40%, respectively, by GC). The isomers were resolved by HPLC on the silver-nitrate column, as described in Example 10.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]2([S:15][CH3:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C[OH:18].O>>[OH:1][C:2]1[CH:3]=[C:4]([C:9]2([S:15]([CH3:16])=[O:18])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CO
Reactant: CSC1(c2cc(O)cc(F)c2)CCOCC1
Solvent: O
Product: CS(=O)C1(c2cc(O)cc(F)c2)CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a stirred solution of 4-(3-hydroxy-5-fluorophenyl)-4-methylthio-3,4,5,6-tetrahydro-2H-pyran (749 mg, 3.1 mmol)(EP 462830 A2 (1991)) in methanol-water (1:1.v/v; 20 ml) cooled to 0° C. was added NalO4 (710 mg, 3.3 mmol), the ice bath removed and the mixture stirred at room temperature for 2 hours. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (50 ml). The organic extract was washed with water (50 ml), brine (50 ml), dried (MgSO4) and concentrated in vacuo. The residual solids were purified by column chromatography on silica gel (SiO2, 150 g; ethyl acetate) to afford 752 mg (94%) of the titled compound as white solids.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH:21]([C:30]1[C:34]([CH:35]2[CH2:37][CH2:36]2)=[C:33]([CH:38]2[CH2:41][CH:40]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:39]2)[O:32][N:31]=1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(O)(=O)C.O>[CH:35]1([C:34]2[C:30]([CH:21]([CH2:20][CH2:19][OH:18])[CH2:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[N:31][O:32][C:33]=2[CH:38]2[CH2:39][CH:40]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:41]2)[CH2:36][CH2:37]1
Reactant: CC(C)CC1CC(c2onc(C(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC(=O)OC(C)(C)C)c2C2CC2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)CC1CC(c2onc(C(CCO)CC(=O)OC(C)(C)C)c2C2CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.9 %

Procedure:
tert-Butyl 5-(tert-butyldiphenylsilanyloxy)-3-[4-cyclopropyl-5-(3-isobutylcyclobutyl)isoxazol-3-yl]valerate (17.62 g) and tetrahydrofuran (106 mL) were mixed. After an addition of acetic acid/water=4/1 (2.45 mL) and tetrabutylammonium fluoride (1 M in tetrahydrofuran) (39.2 mL) to the solution at ice temperature, the mixture was stirred at RT overnight. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/6→1/2) to give the title compound (11.82 g).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[N:2].O.Cl[CH2:12][C:13]([OH:15])=[O:14]>C(OCC)(=O)C>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH2:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(O)CCl
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(NCC(=O)O)cc1
Temperature: 100 °C

Procedure:
In a 500-ml three-necked flask, 4-cyanoaniline (100 g, 847.4 mmoles) was placed, followed by addition of 300 ml of water and attachment of a water cooling pipe, a mechanical stirrer and a dropping funnel. The flask was heated on an oil bath heated at 100° C. To the flask, an aqueous solution (water 150 ml) of monochloroacetic acid (104 g, 1116 mmoles) was added dropwise for about 30 minutes, followed by reflux with heating for 2.5 hours. After cooling naturally, about 100 ml of ethyl acetate was added to the flask to dissolve an insoluble matter. An organic layer was separated by a separatory funnel. The residual water layer and an aqueous layer obtained by extracting the organic layer with 100 ml of 5% (by weight) NaOH solution were combined, followed by acidolysis with 1/10N HCl. A precipitate produced was filtered and washed with water several times. After drying in an oven heated at 60° C. for 3 hours, the dried precipitate was dried in a vacuum desiccator overnight. The resulting product was a beige powder which showed no melting point but decomposed at 233.1° C. The yield was 38.8 g (26%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[OH:12][CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1>>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([N:15]2[CH2:16][CH2:17][CH:13]([OH:12])[CH2:14]2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: OC1CCNC1
Product: OC1CCN(c2ccc(C(F)(F)F)cc2)C1
Yield: 55 %

Procedure:
The title compound (2.71 g, yield 55%) was obtained from 4-(trifluoromethyl)phenyl bromide and 3-hydroxypyrrolidine by a method similar to that in Reference Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:27]=[CH:26][C:16]([CH2:17][NH:18]C(=O)OC(C)(C)C)=[CH:15][CH:14]=2)[S:11][CH:12]=1)=[O:7].C(Cl)[Cl:36].Cl>O1CCOCC1>[ClH:36].[NH2:18][CH2:17][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[S:11][CH:12]=[C:8]([C:6]([C:5]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:7])[N:9]=2)=[CH:27][CH:26]=1
Reactant: COc1cc(C(=O)c2csc(-c3ccc(CNC(=O)OC(C)(C)C)cc3)n2)cc(OC)c1OC
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(C(=O)c2csc(-c3ccc(CN)cc3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.3 %

Procedure:
At 0° C., to a solution of 68a (200 mg) in 10 ml, CH2Cl2 was added a solution of HCl in 1,4-dioxane (4 N, 2 mL) and stirred at RT for 4 h. The precipitate (2r) was filtered and washed with diethyl ether. Yield: 81.3%. 1H NMR (500 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.38 (br, 3H), 8.10 (d, 2H, J=8.4 Hz), 7.66 (d, 2H, J=8.4 Hz), 7.62 (s, 2H), 4.11 (s, 2H), 3.87 (s, 6H), 3.80 (s, 3H). MS (ESI) m/z 385.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][NH2:13].[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH2:31][C@H:30]([CH3:34])[CH2:29]2)[CH:21]=[CH:20][C:17]=1[CH:18]=O>>[F:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[C:18]([C:17]1[CH:20]=[CH:21][C:22]([O:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][C@H:30]([CH3:34])[CH2:29]3)=[CH:23][C:16]=1[O:15][CH3:14])[N:13]([CH3:12])[C:4]2=[O:6]
Reactant: CN
Reactant: COc1cc(OCCCN2CCC[C@H](C)C2)ccc1C=O
Reactant: Nc1c(F)cccc1C(=O)O
Product: COc1cc(OCCCN2CCC[C@H](C)C2)ccc1-c1nc2c(F)cccc2c(=O)n1C

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 2-amino-3-fluorobenzoic acid, methylamine and 2-methoxy-4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}benzaldehyde.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[C:12]([O:14][CH3:15])=[O:13])=[O:5])[CH3:2].C(N(CC)CC)C.[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1.[H][H]>ClCCl.C(OCC)(=O)C.[Pd]>[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([CH2:2][CH2:1][O:3][C:4]([CH2:6][NH:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[NH2:19])[C:12]([O:14][CH3:15])=[O:13])=[O:5])=[O:35])=[CH:32][CH:31]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: [H][H]
Reactant: CCOC(=O)CNCc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)c(CNCC(=O)OCCC(=O)c2ccc(Cl)cc2)c1
Reaction time: 8 h

Procedure:
2.2 g (6.14 mmol) of methyl 3-[(ethoxycarbonylmethylamino)-methyl]-4-nitrobenzoate was dissolved in 50 ml of dichloromethane. 4 mg (0.023 mmol) of 2-chloro-1,3-dimethylimidazonium chloride, 1.29 ml (9.2 mmol) of triethylamine and 1.16 g (7.3 mmol) of 4-chlorobenzoic acid were added to the obtained solution, and they were stirred overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was dissolved in 20 ml of ethyl acetate. 200 mg of 10% palladium/carbon was added to the obtained solution and they were stirred in the presence of hydrogen at room temperature for 5 hours. The reaction mixture was filtered through Celite and the solvent was evaporated to obtain the crude product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.Cl.CN.C[CH2:17][N:18](C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([NH:18][CH3:17])[N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNc1cc(C(=O)OC)nc(Cl)n1
Reaction time: 1 h

Procedure:
To a mixture of methyl 2,6-dichloropyrimidine-4-carboxylate (2 g), methylamine hydrochloride (0.72 g) in CH2Cl2 (48 mL) at 0° C. was added Hunig's base (3.7 mL) dropwise, and the reaction mixture was stirred at ice bath for 1 h and then rt for 1 h. The solvent was removed in vacuo, and the white residue was purified directly by Biotage eluting with 40-600% EtOAc/Hexanes (1000 mL) followed by 90% CH2Cl2/10% MeOH (4 L) to give the title compound as a white solid (1.8 g). These fractions were combined and evaporated in vacuo. During the solvent removal, some white solid was formed. Several filtrations gave the title compound as a white solid (1.8 g, very white solid). LC-MS (M+H)+=202.00
Reaction SMILES: C(OCC[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:22]=2)[N:17]=[C:16]1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)(=O)C.[OH-:38].[Li+].O.Cl.O1CCCC1[CH2:47][CH2:48][OH:49]>>[CH3:37][O:36][C:32]1[CH:31]=[C:30]([C:16]2[N:15]([CH2:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][CH2:47][C:48]([OH:49])=[O:38])[C:23]3[C:18]([N:17]=2)=[N:19][CH:20]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=3)[CH:35]=[CH:34][CH:33]=1
Reactant: [OH-]
Reactant: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3n2Cc2ccccc2OCCOC(C)=O)c1
Reactant: OCCC1CCCO1
Agent: Cl
Agent: [Li+]
Solvent: O
Product: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3n2Cc2ccccc2OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
[2-[[2-(3-methoxyphenyl)-6-phenyl-1H-imidazo[4,5-b]pyridin-1-yl]methyl]phenoxy]ethyl acetate (Compound of Example 158) (28 mg) was dissolved in tetrahydrofuran-ethanol (1:1, v/v, 3.6 ml), and to the solution was added 2 N lithium hydroxide (1.2 ml). The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and to the mixture was added 2 N hydrochloric acid to adjust the pH to 3. The mixture was extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried over MgSO4. The solvent was distilled off under reduced pressure and the resulting crystals were collected by filtration to obtain [2-[[2-(3-methoxyphenyl)-6-phenyl-1H-imidazo[4,5-b]pyridin-1-yl]methyl]phenoxy]acetic acid (15 mg, 55%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH:4]=[CH:5][CH2:6][OH:7].[C:9]([Si:13](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:12])([CH3:11])[CH3:10]>O1CCCC1>[C:9]([Si:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[O:7][CH2:6][CH:5]=[CH:4][CH2:3][OH:8])([CH3:12])([CH3:10])[CH3:11]
Reactant: OCC=CCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCC=CCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
NaH (3 g, 75 mmol, 60% in oil) was added portion-wise to a stirred and cooled (0° C.) solution of but-2-ene-1,4-diol (6 g, 68.09 mmol) in dry tetrahydrofuran (250 mL). After the addition, the mixture was allowed to warm to room temperature and stirred for another two hours. The resulting white mixture was then cooled (0° C.) and tert-butyl-chlorodiphenylsilane (15.7 mL, 61.28 mmol) was added drop wise. After twenty minutes, the cooling bath was removed and the mixture was allowed to stir overnight at room temperature. Saturated NH4Cl was poured into the reaction mixture and the reaction was partitioned with diethyl ether (200 mL). The organic layer was washed with brine, dried (MgSO4), and filtered. The resulting oil was used in the following step without further purification.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].CC(C)=O.[OH-].[Na+:37]>CCO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:37]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Yield: 80.8 %

Procedure:
Fluvastatin methyl ester (3.0 g) was added to acetone (30 ml) and the solution was stirred at room temperature. NaOH (1 eq.) in EtOH (3 ml) was added to the solution. The mixture was stirred overnight. The product that precipitated was isolated by filtration under nitrogen, washed with acetone (100 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 2.45 g (80.8%) of fluvastatin sodium Form XLIV.
Reaction SMILES: [NH2:1][CH2:2][C@:3]1([CH2:18][OH:19])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17].[C:20]([NH:23][CH2:24][C:25](O)=[O:26])(=[O:22])[CH3:21].[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:20]([NH:23][CH2:24][C:25]([NH:1][CH2:2][C@:3]1([CH2:18][OH:19])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17])=[O:26])(=[O:22])[CH3:21]
Reactant: CC(=O)NCC(=O)O
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@](CN)(CO)O2)c(=O)[nH]c1=O
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCC(=O)NC[C@]1(CO)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4′-C-(Aminomethyl)thymidine (4) (0.025 g, 0.1 mmol), N-acetylglycine (0.023 g, 0.2 mmol) and TSTU (0.09 g, 0.3 mmol) were dissolved in anhydrous N,N-dimethylformamide (1 mL) at ambient temperature. Diisopropylethylamine (0.065 g, 0.5 mmol, 0.087 mL) was then added and the reaction mixture stirred for 18 hours at ambient temperature. The solvent was then removed under vacuum and the residue re-dissolved in 9:1 dichloromethane:methanol and eluted through a flash silica gel column with 9:1 dichloromethane:methanol. The title compound (19) was obtained as an amorphous solid on removal of solvent from the appropriate fractions (0.023 g). δH(300 MHz, CD3OD) 7.78(1H, s, H-6), 6.26(1H, dd, H-1′), 4.48(1H, dd, H-3′), 3.83(2H, s, glycyl CH2), 3.60(2H, 2d, H-5′), 3.58(1H, d, 4′-C—CH2), 3.42(1H, d, 4′-C—CH2), 2.33(2H, m, H-2′), 2.00(3H, s, CH3CO), 1.86(3H, s, 5-CH3); ES +ve m/z 393(M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40][C:41](=[O:47])OC(Cl)(Cl)Cl)Cl.[F:49][C:50]1[CH:57]=[CH:56][C:53](CO)=[CH:52][CH:51]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:40][CH2:38][C:53]2[CH:56]=[CH:57][C:50]([F:49])=[CH:51][CH:52]=2)=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: OCc1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCc4ccc(F)cc4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 62.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (72 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (108 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-fluorobenzyl alcohol (40 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (68 mg, yield 58%).
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=[CH:7][N:6]=1.O>CN(C=O)C>[CH3:1][S:2][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=[CH:7][N:6]=1
Reactant: C[S-]
Reactant: Clc1cc(-c2ccccc2)ncn1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(-c2ccccc2)ncn1
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
To a suspension of sodium methanethiolate (0.88 g) in dry DMF (15 ml) at 0° C. was added dropwise over 20 minutes a solution of 4-chloro-6-phenylpyrimidine (2.18 g) in dry DMF (25 ml). Ater stirring for a further 15 minutes, the temperature was allowed to rise to room temperature. After 2 hours the reaction mixture was poured into water and extracted with ether (×3). The combined ether extracts were washed with water (×2), dried, filtered and evaporated to give 4-methylthio-6-phenylpyrimidine (2.16 g, 87% pure by GC analysis) as a yellow liquid which was used directly in the next stage.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:20]=[N:21][N:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:23]=3[C:24]([F:27])([F:26])[F:25])[O:16][N:15]=2)=[CH:10][CH:9]=1)[C:3]([O:5]CC)=[O:4].CO.[Li+].[OH-]>C1COCC1>[OH:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:20]=[N:21][N:22]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:23]=3[C:24]([F:25])([F:26])[F:27])[O:16][N:15]=2)=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
(R/S)-Ethyl 2-hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetate (Int-VI, 1.95 g, 4.25 mmol) was dissolved in THF (11 mL) and MeOH (5.50 mL) was added. Then, 1N LiOH (4.25 mL, 4.25 mmol) was added. It was stirred for 10 min and additional 1N LiOH (0.85 mL, 0.85 mmol) was added. After 10 min, more 1N LiOH (0.42 mL, 0.42 mmol) was added. After stirring for 10 min, the solution was concentrated and then EtOAc was added. The EtOAc was washed with 1 N HCl aqueous. The organic layer was dried (MgSO4), filtered and concentrated to give (R/S)-2-hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-VII, 1.8 g, 4.1 mmol, 97%): LCMS=431.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[N:24][CH:25]=1.O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:26][C:22]1[CH:23]=[N:24][CH:25]=[C:20]([Cl:19])[CH:21]=1)[CH3:2]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: Oc1cncc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccnc1Oc1cncc(Cl)c1
Temperature: 25 °C
Yield: 32 %

Procedure:
A solution of 2-Chloro-nicotinic acid ethyl ester (2.07 grams, 11.2 mmole), Cesium carbonate (7.27 grams, 22.3 mmole) and 5-chloro-3-pyridinol (1.45 grams, 11.2 mmole) in dry dimethylformamide (40 ml) was stirred at 90° C. overnight. The suspension was cooled to room temperature, poured into water and extracted with diethyl ether. The combined organics were washed with water and brine, dried over MgSO4, and concentrated to a tan solid. Recrystalization from hexane gave a yellow solid (1.0 g). M.P. 65-69° C.; Anal. calcd. for C13H11ClN2O3: C, 56.03; H, 3.98; N, 10.05. Found: C, 56.14; H, 4.04; N, 10.16.